The .beta.-adrenergic agonist hormones when bound to plasma membrane adrenergic receptor sites (.beta.-sites) produce a broad range of physiological effects such as vasodilation, changes in blood pressure, cardiac stimulation resulting in enhanced cardiac output and rate, increased production of glucose, and initiation of glycogenolysis, etc. These hormones, from a chemical standpoint, are generally classified as catecholamines. That is, they usually possess the characteristic hydroxyl groups substituted at the 3- and 4-positions on a benzene ring and an hydroxyethylamine side chain attached to the number 1 position of the benzene ring.
This invention was made with Government support under Grant No. HL 26340 awarded by the Department of Health and Human Services. The Government has certain rights in this invention.
As noted in U.S. Pat. No. 4,337,207 a number of recently developed derivatives of the naturally occurring catecholamine .beta.-agonist hormones are also capable of producing significant biological and pharmacological effects. Such derivatives include chemically modified and extended hydroxyethylamine side chains wherein an alkyl or alkylaryl chain of variable length is added to the amine and terminates in a carboxylic acid or carboxylic acid derivative functional grouping.
In the past several decades, a group of hormone-like molecules has been synthesized that may also bind at the same .beta.-sites and thereby interfere with, or eliminate, the effects of the .beta.-agonist hormones. These ".beta.-adrenergic antagonist" molecules also play a useful role in the control of the physiological and pathological processes related to this complex hormonal system. For instance, these .beta.-antagonists, when administered to a patient can reduce high blood pressure (hypotensive), restore regular heart rhythm, reduce myocardial work and therefore myocardial oxygenation i.e., they are antianginal.
Like the .beta.-adrenergic agonist hormones, the ".beta.-adrenergic antagonists" may act at both so-called .beta..sub.1 receptor sites and .beta..sub.2 -receptor sites. The .beta..sub.1 -receptors are generally associated with heart function (e.g. force of contraction); while the .beta..sub.2 -receptors are usually associated with bronchial smooth muscle and skeletal muscle. The .beta.-adrenergic antagonists therefore may be classified as "nonselective" when they act at both .beta..sub.1 - and .beta..sub.2 -receptors; or "cardioselective" (or .beta..sub.1 -selective) when they act predominantly at .beta..sub.1 -receptors. In many instances it is desirable to have cardioselective .beta.-adrenergic antagonists available for therapy.
The most common .beta.-adrenergic antagonists have quite closely-related structures that can most often be represented by the general formula: ##STR2## where R.sub.1 is an aryl, or substituted aryl group and R.sub.2 is most commonly an isopropyl group; and in a limited number of cases, t-butyl. (In a more limited number of cases .beta.-adrenergic antagonists may be represented by the general formula: ##STR3## where R.sub.1 is a substituted aryl group and R.sub.2 is generally isopropyl).
The most common non-selective .beta.-adrenergic antagonists include: ##STR4## The most common cardioselective .beta.-adrenergic antagonists include: ##STR5##
In any event all .beta.-adrenergic antagonists exhibit related .beta.-adrenergic properties when introduced into the vascular system. While the structures produce qualitatively similar, but quantitatively different pharmacological effects, in some instances, these effects are diverse and general, but, in others, the effects are very specific. These differences often relate to the different selectivities discussed above.
It is therefore of interest to explore the possibility of devising modified .beta.-adrenergic antagonist molecules which will exhibit biological activities similar to those of the parent compounds; but which might also exhibit enhanced (increased potency), or prolonged (in vivo) activity; or perhaps selective effects which would permit the "targeting" of the drugs or drug effects to selected receptors, tissues, or cells within tissues or a more selective basis than is possible with the parent molecules; or to selected clinical uses wherein the drug effects are narrowed by means of pharmacodynamic or pharmacokinetic differences from the native drug.
It would also be of great interest if structurally modified .beta.-antagonists could be further conjugated with other carrier molecules, e.g., defined peptides or proteins, whereby the conjugate molecules might be degraded less readily by enzymes; or greater tissue or receptor specificity might be imparted because of the drug-carrier properties. The receptors for the .beta.-antagonists are located on the outer surface of cell membranes, and the observed biological effect of the attachment of the antagonists to carrier molecules need not be predominantly dependent upon, nor necessarily be complicated by, complex membrane transport phenomena or phagocytosis of a conjugate molecule. It is therefore possible for covalent conjugates of the .beta.-antagonists to reach the .beta.-receptor sites intact as have their agonist counterparts.